HLA class II‐associated genetic susceptibility in multiple sclerosis: A critical evaluation

Abstract

Multiple sclerosis (MS) has, since the 1970s, been known to be associated with the HLA-Dw2 and -DR2 specificities in Caucasian Europeans and North Americans. By the use of genomic typing techniques, the association has been specified to be with the DRw15,DQw6,Dw2, i.e. the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. A significant DPw4 association in Scandinavian MS patients has been described in one report. However, this association has not been confirmed in several subsequent studies with patients from the same and other ethnic groups. During the last few years several reports, based on serological, RFLP and PCR-SSO data, have suggested that the HLA class II-associated MS susceptibility gene(s) may be more closely associated with the DQ than with the DR subregion. The observations that the HLA-DQB1 genes of MS patients share long stretches of sequence motifs and also carry DQA1 alleles encoding glutamine at position 34 of the DQ alpha chain have received considerable attention. It has been suggested that the susceptibility to develop MS might be determined by the corresponding DQ alpha-beta heterodimers either encoded in cis or in trans. We have investigated these issues in a large group of Swedish MS patients (n = 179). We found that the associations with the suggested DQB1 sequences and position 34 of the DQ alpha chain were due to linkage disequilibrium and secondary to the association with the DRw15,DQw6,Dw2 haplotype (p less than 10(-9) and p less than 10(-8), respectively). No overrepresentation of the implicated DQ alpha-beta heterodimers was observed in DRw15,DQw6,Dw2-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetics of primary progressive multiple sclerosis

“…In a follow-up case-control study of 179 Swedish patients and 250 controls, these investigators confirmed the association with HLA-DRw15 (HLA-DRB1*1501) and MS in both PPMS and RRMS patients relative to healthy controls (OR ¼ 3.99, p < 0.0001) (Olerup and Hillert, 1991). When the 36 PPMS patients were considered separately, the association with HLA-DRw15 persisted (OR ¼ 3.27, p ¼ 0.001), as did the association in RRMS (OR ¼ 4.2, p < 0.0001).…”

Genetic aspects in sarcoidosis

“…A similar negative result was more recently reported by MALIARIK et al [61] in 69 African-American patients with sarcoidosis, in which the frequency of HLA-DPGlu 69 was only slightly increased over that in controls. The same authors did, however, report a weak association for Val 36 (OR=2.30) and for Asp 55 (OR=2.03), suggesting that such residues may contribute to sarcoidosis susceptibility in African-Americans. In contrast, in 41 British subjects with sarcoidosis, LYMPANY et al [62], although unable to find an association with HLA class II alleles or to confirm the association with the DPB1 position 55, reported that 26/47 sarcoid subjects had DPB1*Glu 69 alleles, this being a significantly higher frequency than that in the controls (p<0.02).…”

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

“…3 Within the MHC, the human leukocyte antigen (HLA) DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 haplotype has a pre-eminent role, especially for populations of Northern European descent. [4][5][6][7] However, there is now robust, validated evidence that other variants within the MHC have independent roles in rendering individuals susceptible to MS, 8 and there is evidence for a role of the MHC in age at onset 9 and disease course. 10,11 Many studies have used clinical measures of severity to explore this aspect, but MRI-derived measures (such as brain atrophy and T 2 -weighted lesion volume or T2LV) appear to be more sensitive in capturing the course of disease, particularly in the early years after symptom onset.…”